AN0025, a novel antagonist of PGE2-receptor E-type 4 (EP4), in combination with total neoadjuvant treatment of advanced rectal cancer

Saunders, Mark; Hall, Marcia; Ng, Jmk; Hong, Theodore S.; Xu, Shuoyu; Lucas, Judy; Lu, Xuhang; Lautermilch, N; Formenti, S.C.; Glynne‐Jones, Robert

doi:10.1016/j.radonc.2023.109669

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2024

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Cited by 3 publications

References 31 publications

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Revisiting prostaglandin E2: A promising therapeutic target for osteoarthritis

Yang,

Xu,

et al. 2024

Clinical Immunology

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Revisiting prostaglandin E2: A promising therapeutic target for osteoarthritis

Yang,

Xu,

et al. 2024

Clinical Immunology

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Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells

Punyawatthananukool,

Matsuura,

Wongchang

et al. 2024

Nat Commun

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RMX1002 as monotherapy and in combination with anti-PD-1 antibody in advanced solid tumors: a phase I dose-escalation and expansion study

Liu,

Gong,

Zhang

et al. 2024

Preprint

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Background: RMX1002 (grapiprant) is a selective E-type prostanoid receptor 4 (EP4) antagonist and a promising candidate for cancer therapy, potentially enhancing anti-tumor immune responses. This study aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of RMX1002 as monotherapy and in combination with anti-PD-1 antibody toripalimab for advanced solid tumors. Patients and Methods: This multicenter, phase I trial enrolled patients with histologically or cytologically confirmed advanced solid tumors. This study included three phases: Ia (dose-escalation of RMX1002 monotherapy from 200 to 650mg BID), Ib (dose-escalation from 500 to 650mg BID in combination with toripalimab), and Ic (dose-expansion of 500mg BID with toripalimab). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. Results: A total of 45 patients were enrolled (17 in phase Ia, 12 in phase Ib, and 16 in phase Ic). No dose-limiting toxicity was reported, and the MTD was not reached. Overall, 21 patients experienced RMX1002-related adverse events with CTCAE grade ≥3. Pharmacokinetics revealed rapid absorption of RMX1002 with the maximum concentration (Cmax) reached within 2 to 5 hours, and dose-dependent increases in Cmax and area under the concentration-time curve. The increase in urinary metabolite of PGE2 suggested the inhibition of EP4 signaling pathway. The best response of stable disease was reported in 64.7%, 28.6%, and 18.8% of patients in phase Ia, Ib, and Ic, respectively. Conclusion: RMX1002 was well tolerated at the tested doses and showed signs of antitumor activity. RMX1002 500 mg BID with toripalimab 240 mg biweekly was selected as the recommended dose for future clinical trials.

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AN0025, a novel antagonist of PGE2-receptor E-type 4 (EP4), in combination with total neoadjuvant treatment of advanced rectal cancer

Cited by 3 publications

References 31 publications

Revisiting prostaglandin E2: A promising therapeutic target for osteoarthritis

Revisiting prostaglandin E2: A promising therapeutic target for osteoarthritis

Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells

RMX1002 as monotherapy and in combination with anti-PD-1 antibody in advanced solid tumors: a phase I dose-escalation and expansion study

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